bims-mecosi 2023-09-17 papers

Issue of 2023‒09‒17
five papers selected by
Verena Kohler, University of Graz

bioRxiv. 2023 Aug 28. pii: 2023.08.28.555163. [Epub ahead of print]

Orthogonal targeting of SAC1 to mitochondria implicates ORP2 as a major player in PM PI4P turnover.

Colleen P Doyle, Andrew Rectenwald, Liz Timple, Gerald R V Hammond.

Oxysterol binding protein (OSBP)-related proteins (ORPs) 5 and 8 have been shown to deplete the lipid phosphatidylinositol 4-phosphate (PI4P) at sites of membrane contact between the endoplasmic reticulum (ER) and plasma membrane (PM). This is believed to be caused by transport of PI4P from the PM to the ER, where PI4P is degraded by an ER-localized SAC1 phosphatase. This is proposed to power the anti-port of phosphatidylserine (PS) lipids from ER to PM, up their concentration gradient. Alternatively, ORPs have been proposed to sequester PI4P, dependent on the concentration of their alternative lipid ligand. Here, we aimed to distinguish these possibilities in living cells by orthogonal targeting of PI4P transfer and degradation to PM-mitochondria contact sites. Surprisingly, we found that orthogonal targeting of SAC1 to mitochondria enhanced PM PI4P turnover independent of targeting to contact sites with the PM. This turnover could be slowed by knock-down of soluble ORP2, which also has a major impact on PM PI4P levels even without SAC1 over-expression. The data reveal a role for contact site-independent modulation of PM PI4P levels and lipid antiport.

DOI: https://doi.org/10.1101/2023.08.28.555163

Cell Mol Biol (Noisy-le-grand). 2023 Jul 31. 69(7): 138-142

High glucose-induced imbalance of mitochondria-associated ER membranes function promotes RSC96 cell damage.

Housheng Fu, Jianbing Xu, Fei Wang, Weifu Wang, Zhongyao Wang.

To investigate the effect of high glucose on mitochondrial-related ER membranes (MAMs) in rat Schwann cells (SCs) and the mechanism of cell injury. SCs (RSC96) cells were used as the control group, and RSC96 cells cultured in a high glucose environment for 48 h were set as the experimental group. The level of intracellular calcium was observed by flow cytometry, and ROS levels were detected by DCFH-DA fluorescent probe. The subcellular structure was observed by transmission electron microscopy, focusing on the morphology of mitochondria and endoplasmic reticulum as well as the formation of MAMs. The expression levels of MAMs-related proteins Mfn2, PERK, VDAC1, and IP3R were detected by Western blot. Compared with the control group, after high glucose-induced cells, the level of calcium ion was significantly increased (p<0.01), the level of ROS was significantly increased (p<0.01), mitochondria and endoplasmic reticulum were damaged, and the number of MAMs was increased (p<0.05). Western blot analysis showed that the expression level of Mfn2 was significantly decreased (p<0.01), and the expression levels of PERK, VDAC1, and IP3R were significantly increased (p<0.01). By inducing the imbalance of MAMs function in SCs, high glucose promotes intracellular calcium overload and leads to cell damage.

DOI: https://doi.org/10.14715/cmb/2023.69.7.22

Arch Biochem Biophys. 2023 Sep 09. pii: S0003-9861(23)00242-4. [Epub ahead of print]747 109743

Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats.

Fangmei Luo, Minyi Fu, Ting Wang, Yanan Qi, Xuefeng Zhong, Dai Li, Bin Liu.

BACKGROUND: Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear.METHODS AND RESULTS: We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy.
CONCLUSIONS: The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.

Keywords: Maladaptive right ventricular remodeling; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial dynamics; Mitofusin 2; Optic atrophy 1; Pulmonary hypertension

DOI: https://doi.org/10.1016/j.abb.2023.109743

Am J Pathol. 2023 Sep 07. pii: S0002-9440(23)00314-0. [Epub ahead of print]

The Role of Endoplasmic Reticulum in Lipotoxicity during MASLD Pathogenesis.

Nanditha Venkatesan, Luke C Doskey, Harmeet Malhi.

Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic-dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: Inositol Requiring Enzyme1α, PKR-like ER Kinase and Activating Transcription Factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER-nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. In this review, lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis is discussed.

Keywords: endoplasmic reticulum stress; lipotoxicity; metabolic liver disease; nonalcoholic steatohepatitis; unfolded protein response

DOI: https://doi.org/10.1016/j.ajpath.2023.08.007

J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):

A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.

Arisa Ikeda, Miho Iijima, Hiromi Sesaki.

Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.

DOI: https://doi.org/10.1083/jcb.202309037